Project Summary Obesity and its associated complications impose a huge burden to our society. However, the mechanisms underlying this disorder and its related pathologies remain unclear, and effective treatments are still lacking. At its core, obesity results from an imbalance between energy intake and energy expenditure. Most work has focused on neural regulation of energy balance, however, an important but poorly understood element is the role played by astrocytes in the regulation of energy states although they play crucial functions in regulating synaptic strength and neural activity. To further our understanding of the processes of obesity and to seek effective therapeutics, it is necessary to consider astrocytic influence on energy homeostasis and determine the underlying mechanisms. Our long-term goal is to enable the development of novel targets to correct diet-induced obesity (DIO). Our overall objective for this application is to determine the ability of hypothalamic astrocytes to correct DIO and determine the mechanisms of that correction. Our central hypothesis is that astrocyte can react to and negatively regulate energy surfeit in DIO by reducing the synaptic strength at orexigenic agouti-related protein (AgRP) neurons in arcuate nucleus (ARC) in mice, which will be achieved by elevating extracellular adenosine. Our hypothesis has been formulated on the basis of our recent study and our preliminary data that astrocyte activation reduces feeding and silences AgRP neurons via adenosine A1 signaling, induces energy expenditure, and elevates extracellular adenosine. The rational for the proposed research is that, once it is known how astrocytes regulate energy states, it may be feasible to manipulate them pharmacologically to correct or reverse obesity, and potentially a variety of eating disorders. To accomplish our goals, we have assembled a research team that combines a diverse range of expertise including glial biology, neurobiology, and energy metabolism. To test our central hypothesis and thereby accomplish our overall objective, we will carry out three Specific Aims: (1) Determine how astrocytes control synaptic strength at AgRP neurons; (2) Determine how astrocytes contribute to synaptic alterations during (HFD) feeding; (3) Identify astrocytic target in the treatment of HFD-induced obesity (DIO). Experiments proposed here will be examined using a multifaceted approach that includes cell type-specific electrophysiology, chemogenetic- and optogenetic astrocytic manipulation, time-lapse deep-brain measurements of adenosine, temporal control of pharmacology, and metabolic assays. Adenosine augmentation therapy in obesity will also be performed with an integrated chemical and genetic approach to target adenosine kinase inhibitor to arcuate astrocytes. Results using these cutting-edge methods will give us unprecedented access to understanding glial control of energy states. Together, the proposed research represents a new and substantial departure from other studies in that it shifts the focus to developing astrocytic targets for obesity treatment.